Simulated moving bed chromatography (SMB) was first described in U.S. Pat. No. 2,985,589. The specification discloses a separation tower divided into a number of individual interconnecting separation beds containing solid phase chromatography substrates. An inline pump at the bottom of the tower connects flow from the bottom to the top, thereby providing a continuous loop. Inlet ports for feedstock (F) and Desorbent (D) and exit ports for Raffinate (R) and Extract (E) are placed at specific points in the series of separation beds. At defined intervals, the position of the beds is switched in the opposite direction from the flow, producing a countercurrent movement of the solid phase beds relative to the fluid streams. Feedstock (F) introduced into the first bed begins to separate into components contained therein as flow ensues, with less retained species migrating in the direction of fluid flow and being collected at the Raffinate port. The more retained species remain preferentially associated with the solid phase and are collected at the Extract port. By regulating the switch times and flow rates of F, D, R, and E, a standing wave pattern is established, allowing for continuous flow of purified products from the system.
The basic SMB process is further illustrated schematically in FIG. 1. At the top of the diagram, feed depicted as a mixture of solid and open circles is introduced between chromatographic columns 1 and 8 with the direction of fluid flow clockwise, and column switching counterclockwise. In Zones II and III (columns 7, 8, 1, and 2) separation of species occurs, and the open circles exit the system in the raffinate at the three o'clock position. Desorbent is introduced at six o'clock, and flows clockwise into the system. As the columns rotate, purified closed circle species is drawn off in the extract at the nine o'clock position.
Historically, SMB has been typically applied to large scale industrial binary separations. The process in the '589 patent was applied to the industrial scale separation of cyclohexane from n-hexane. More recently SMB has found favor in separating sugar isomers, hydrocarbons, solvents, and other industrial applications. Many of these industrial devices, like the original '589 device, employ variations of mechanical rotary valves in effecting column switching. The valve components are arranged so that at any given valve position, multiple inlet and outlet flows are directed to predetermined columns, and advanced one position correspondingly with each rotational step. Such rotary valves are disclosed in U.S. Pat. Nos. 6,719,001, 4,574,840, and 4,614,205. To emphasize the intended scale of some of these devices, refer to U.S. Pat. No. 3,040,777 which describes a valve occupying an area of 64 sq. feet and weighing 10 tons.
One of the frequent problems with rotary valves is a tendency to leak at the junction of the rotating member and the stator element. To eliminate this problem many attempts have sought to replace a mechanical valve with a complex series of interconnecting individual valves. Two such valve systems are disclosed in U.S. Pat. Nos. 4,434,051 and 5,635,072. For scale-down of SMB using networks of individual valves, another problem arises, namely, accumulating too much void volume in the connecting lines which interferes with separation. Another U.S. Pat. No. 6,544,413, however, discloses a plural valve device having clustered valve assemblies of four valves for control of inputs/outputs proximately to each chromatographic bed. It has the advantage of reducing volume of liquid for small scale SMB systems. U.S. Pat. No. 6,979,402 discloses a device in which cross-over conduits are replaced entirely by connecting channels machined into the top and bottom plates of the rotary valve body and aligned with column ports to create an SMB fluid loop, thus reducing void volume. However, it is unclear from this disclosure how small the contact surface of the valve components can be to obtain adequate sealing.
There has been a recent trend in scaling SMB down to pilot and sub-pilot volumes, as more sophisticated applications have arisen in the fine chemicals and pharmaceutical fields requiring milligram-to-gram level quantities of product. Several recent applications of SMB to the purification of pharmaceutically active diastereomers and enantiomers have been disclosed in U.S. Pat. Nos. 6,462,221, 6,461,858, 6,458,995, and 6,455,736. Uses of new chiral resins in SMB for binary separations of such molecules are becoming commonplace. SMB is also beginning to be considered for purification of biomolecules from complex mixtures. For example, purification of monoclonal antibodies using SMB has been reported in Gottschlich, et al., J. Chromo. A, 765 (1997) 201 and disclosed in WO 2004/024284. Standing wave strategies based on SMB have been developed for insulin purification, as reported by Mun, et al., Biotechnol. Prog., 18 (2000) 1332.
The Protein Structure Initiative is a national effort to determine the three-dimensional structure of a wide variety of proteins. This information will accelerate the discovery of protein function and enable faster development of new therapies for treating genetic and infectious diseases. Begun in 2000, this decade-long project has recently entered its second phase. In the second phase, ten new centers will participate in addition to the first nine. One of the significant challenges is to develop methods of purifying target proteins from complex cell extracts in small (10-100 mg) quantities, in high purity (greater than 90%). Basic structural analyses by techniques such as x-ray crystallography and NMR spectroscopy require that standard. A clear need exists for an SMB device that is capable of purifying target small molecules and biomolecules in low (multi-milligram) amounts which avoid mechanical components that leak and large void volumes that interfere with purity, while embodying the hallmarks of SMB, which are controlled purity and continuous production.